Method for treating emotional or mental illness and emotional or mental illness concomitant with seizures

ABSTRACT

Disclosed herein is a method for treating depression associated with alcoholism in a patient comprising administering to the patient a pharmacologically effective dose of an opioid antagonist, and a pharmacologically effective dose of at least one drug compound selected from the group consisting of a tricyclic antidepressant, an a-typical antidepressant, and lithium.

This application is a continuation of Ser. No. 08/755,795, filed Aug.28, 1996, now U.S. Pat. No. 5,856,332, which is a divisional of Ser. No.08/560,820, filed Nov. 20, 1995, now U.S. Pat. No. 5,817,665, which is adivisional of Ser. No. 08/031,096, filed Mar. 2, 1993, now U.S. Pat. No.5,512,593.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to the use of an opioid antagonist such asnaltrexone in combination with one or more serotonin(5-hydroxytryptamine or 5-HT) or norepinephrine reuptake inhibitor(s)and/or lithium to treat mental or emotional disorders characterized bydepression, obsessiveness, depression with anxiety, mania, manicdepression, depression with manic episodes, and depression concomitantwith an illness causing seizures which are inhibited by carbamazepine,or a combination of any of these mental or emotional illnesses, ormental or emotional illnesses with seizures. The inventor has discoveredthat naltrexone is useful in combination with lithium and/or one or moreserotonin (5-HT) uptake inhibitor and/or norepinephrine (N.E.) uptakeinhibitor drug compounds in treating patients whose depression and/orassociated mental illnesses or conditions were refractory to drugtreatment using one or more known antidepressant agents or agents formanic and manic depressive disorders such as lithium, and tricyclic anda-typical antidepressants including, but not limited to clomipramine,amitriptyline, imipramine, sertraline and nortriptyline that inhibit5-HT and/or N.E. reuptake.

The inventor has further discovered that such treatment using naltrexonein combination with lithium and/or 5-HT or N.E. reuptake inhibitors iseffective even where benzodiazepines are concurrently administered totreat anxiety. Additionally, the inventor has discovered that lithium incombination with naltrexone in some cases reduces manic and manicdepressive bipolar symptoms.

DESCRIPTION OF THE RELATED PRIOR ART

A general discussion of the effectiveness of tricyclic antidepressantsand non-tricyclic a-typical antidepressants in inhibiting 5-HT and/orN.E. neuronal synaptic reuptake and in treating depression, along withthe pharmacology of these compounds is found in Goodman and Gillman, ThePharmacological Basis of Therapeutics, 7th and 8th Eds. (MacMillan Publ.Co.) Chapt. 19, Section 11 "Drugs Used in the Treatment of Disorders ofMood", incorporated by reference herein. According to the presentinvention, tricyclic antidepressants include, but are not limited to,imipramine, amitriptyline, trimipramine, doxepin, desipramine,nortriptyline, protriptyline, amoxapine, clomipramine, maprotriline, andcarbamazepine, and their pharmaceutically effective salts and esters,such as, but not limited to their hydrochlorides, maleates, tartratesand lactates. Although carbamazepine is approved in the U.S. asantiepileptic, it is chemically related to tricyclic antidepressants,its actions on human brain neurons are not completely known, and for thepresent invention it is classified as a tricyclic antidepressant. See,Goodman and Gillman, The Pharmacological Basis of Therapeutics,referenced above, 7th Ed., page 457 et seq.

According to the present invention, a-typical antidepressants include,but are not limited to, bupropion, sertraline, fluoxetine, and trazodoneand their pharmacologically effective salts and esters, such as, but notlimited to, their hydrochlorides, maleates, tartrates and lactates.

Additional discussion of these drug compounds and their analogs'pharmacologic action in inhibiting 5-HT and N.E. and in treatingdepression is found in the Physician's Desk Reference (PDR), 47th Ed.,1993, published by Medical Economics Co., Inc., Montvale, N.J., indexedby generic compound name and incorporated by reference herein.

The opioid antagonists which may be employed in the present inventionhave been known for use in treatment of opioid overdose and to preventabuse of opioids such as heroin or morphine. The pharmacology of opioidantagonist compounds are described in Goodman and Gillman,Pharmacological Basis of Therapeutics, 7th & 8th Eds. (as noted above),Chapt. 22, "Opioid Antagonists", incorporated by reference herein, andinclude, but are not limited to cyclazocine, naloxone, opioid antagonistcompounds having the same pentacyclic nucleus as nalmefene, naltrexone,nalmefene, nalorphine, nalbuphine, thebaine, levallorphan, pentazocine,oxymorphone, butorphanol, buprenorphine, levorphanol, meptazinol,dezocine, and pentazocine and their pharmacologically effective saltsand esters such as, but not limited to their hydrochlorides, maleates,tartrates and lactates.

The generally accepted use for opioid antagonists in treatment of humanailments has been for reversing opioid toxicity and overdoes, and inpreventing abuse of opioids, such as heroin and morphine. However,Glover, in U.S. Pat. No. 5,028,612 incorporated by reference herein,discusses use of opioid antagonists, such as naltrexone, in a method fortreating emotional numbness where emotional numbness is "conceptualizedas a biopsychological response to extreme emotional or physical trauma"and is featured by a person's subjective experience of inability to feelemotions, and lack of care and concern for others.

Glover also discloses that naltrexone may be used in treatment ofemotional numbness coupled with other emotional disorders, such as posttraumatic stress syndrome, schizophrenia, depression, anxiety,hypochondria, and psychomotor disorders, although no support for successin treating such patients is disclosed.

Horrobin in U.S. Pat. No. 4,388,324 discloses a method of moderating theeffects of taking alcohol by administering, among other compositions, acomposition of γ-linolenic acid and/or ascorbic acid and/or ethylalcohol and/or opioid antagonist (See, col. 7, lines 30-35). Horrobindiscloses that endogenous opioid excess, suspected in schizophrenia,coeliac diseases and psoriasis may be reversed by opioid antagonistssuch as naloxone (See, U.S. Pat. No. 4,388,32, col. 3, lines 15-19).

SUMMARY OF THE INVENTION

In many cases of profound depression, tricyclic and a-typicalantidepressants and lithium do not provide sufficient relief to patientsso as to prevent suicide ideation or allow the patient to successfullycarry out continuous daily work routines and social routine activities.In some cases of endogenous depression, reactive depression, and in somecases where patients exhibit depression without suicide ideation,tricyclic and a-typical antidepressants and lithium do notsatisfactorily control patient symptoms or condition.

It is an object of the present invention to provide a novel method fortreating depression, obsessiveness, depression with obsessiveness,depression with anxiety, mania, depression associated with bipolarconditions such as manic depression, depression with manic episodes, anddepression concomitant with an illness causing seizures which areinhibited by carbamazepine, or a combination of these mental oremotional illnesses. These mental or emotional illnesses to be treatedmay or may not be successfully treatable with a tricyclic or a-typicalantidepressants or lithium or a benzodiazepine with anti-anxietyactivity or a combination of these agents without concomitant opioidantagonist administration. The novel method of treatment is accomplishedby adding an opioid antagonist drug compound to the drug treatmentregimen for emotional or mental illness or emotional or mental illnessconcomitant with an illness causing seizures. Preferably, the opioidantagonist added to the treatment regimen is naltrexone (Trexan) givenin an amount of 10-150 mg. per day, along with other medication fordepression and/or manic or bipolar disorder.

It has further been determined that such a drug combination using anopioid antagonist or partial antagonist decreases the craving for sugarsand carbohydrates often experienced with conventional tricyclic anda-typical antidepressant therapy.

The amounts of tricyclic or a-typical antidepressant or lithium whichmay be used with opioid antagonist to achieve the invention are dosageamounts typically given in treatment of depression, mania, or manicdepression bipolar conditions well known to physicians treating mentalor emotional conditions and to pharmacists, pharmacologists, and thoseskilled in the art, and further are those as directed by the labellingfor these drugs as found in the 1993 PDR. The amount of opioidantagonist to be administered should be tailored to individual patientneeds but generally is in the range of 10-150 mg/day. However, largerdoses may be given if tolerated well by the patient, as needed.Appropriate and safe dosages for opioid antagonists are generallydiscussed in the PDR for each opioid antagonist and in Goodman andGillman, Pharmacological Basis of Therapeutics, referenced above, andalso may be determined on a molar weight basis equivalent to that for10-150 mg. of naltraxone (Trexan).

The tricyclic antidepressants which may be used in the present inventioninclude, but are not limited, to imipramine, amitriptyline,trimipramine, doxepin, desipramine, nortriptyline, protriptyline,amoxapine, clomipramine, maprotiline, and carbamazepine and theirpharmaceutically effective salts and esters.

The a-typical antidepressants which may be used in the present inventioninclude, but are not limited to, bupropion, sertraline, fluoxetine,trazodone, and their pharmacologically effective esters and salts.

The opioid antagonist which may be used in the present inventioninclude, but are not limited to, naloxone, opioid antagonist having thesame pentacyclic nucleus as nalmefene, naltrexone, nalmefene,nalorphine, nalbuphine, thebaine, levallorphan, oxymorphone,butorphanol, buprenorphine, levorphanol, meptazinol, pentazocine,dezocine, and their pharmacologically effective esters and salts.

The pentacyclic nucleus is exemplified in the structural formula fornalmefene shown below: ##STR1##

The opioid antagonist to be used in the invention may also possess someopioid agonist activity, and thus may be a partial antagonist with someagonist activity (partial agonist activity).

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention relates to the use of opioid antagonists incombination with lithium and/or a tricyclic antidepressant and/or ana-typical antidepressant with and without concomitant administration ofan anti-anxiety agent such as a benzodiazepine to treat emotional ormental illness or emotional or mental illness concomitant with anillness causing seizures.

It has been discovered that such a treatment results in remarkablealleviation of patients' suicide ideation and general depressed state ormania where such depressed or manic condition was refractive totreatment without opioid antagonist but with lithium and/or a tricyclicantidepressant and/or an a-typical antidepressant.

Preferably, in the present invention, the patient is given a dose of 25or 50 mg. of Trexan per day in the morning, depending on the size of thepatient and the severity of the symptoms of depression.

Some patients may experience several days of sleepiness when Trexan isused in combination with tricyclic or a-typical antidepressants and inthese patients an alternative dose would be in the neighborhood of 10 mgtaken at bedtime for the first three days of administration. On thefourth day, 10 mg may be administered and assuring that no sleepiness isevident the dose should be advanced to 25 mg. each morning for the nextfour weeks. In some individuals, especially those experiencing seasonaldepressions, administration at night may be more effective and thateffect would be noted within a few days of switching the time ofadministration following the first month of treatment. After one monthof treatment, some individuals showing a response to the psychotropicmedicine that is being given concurrently may get a response byincreasing the dose of the opioid antagonist. In the case of Trexan, adose of 50 mg. has been effective in getting response to develop.

A number of adverse effects of the administration of psychotropics havebeen observed to diminish upon this combination therapy, most notablythe weight gain associated with long term administration of tricyclics.The effect of using opioid antagonists to augment treatment withpsychotropic medications is not restricted to depressive disorders asattenuation of hostility and irritability by antidepressant medicationshas been enhanced as well as the reduction in anxiety states andobsessive compulsive states. The facilitation of effect is notrestricted to those who are non-responsive to psychotropic agents buthas been observed in those who have had responses which, whilesatisfactory to the patient, were many times improved upon augmentationwith the opioid antagonist.

The patients whose treatment with antidepressants are to be supplementedby benzodiazepine medication experience a dramatic decrease in theirrequirement for those categories of medication upon successfulcombination of the antidepressant being taken with naltrexone. Inseveral cases studied, treatment with the opioid antagonist alone wascompletely unsatisfactory as was treatment with the psychotropicmedication by itself. This phenomena has been noted with amitriptyline(Elavil), clomipramine (Anafranil), imipramine (Tofranil), andsertraline hydrochloride (Zoloft) and Lithium. Promising results havealso been obtained with carbamazepine (Tegretal), and fluoxetine(Prozac).

Patients should be warned about not stopping benzodiazepine medicinessuch as alprazolam (Xanax) or lorazepam (Ativan) without supervisionotherwise their perception of not needing the effects of theseanti-anxiety agents may lead them to stop too abruptly and precipitatewithdrawal symptoms. Occasionally, in the first three to five days ofadministration, patients describe customarily pleasant dreams replacedby anxious or irritable dreams. This phenomena subsides after a fewdays.

The invention will be more fully understood by reference to thefollowing examples.

EXAMPLE 1

A woman in her thirties who had a long history of depression treatmentfailure requested new treatment. She had, at various times, beenbulimic, self-mutilating, alcoholic, and subject to obsessive thoughts.She had recurrent major depressive episodes which includedcharacteristic vegetative signs of disturbed sleep, decreased appetite,energy, ability to concentrate and remember as well as the affectivesymptoms of sadness, irritability, and intense anxiety. At the time newtreatment was begun, she presented symptoms of depression and insomnia.A variety of antidepressants were tried, the last being clomipraminehydrochloride (Anafranil), approved as an anti-obsessive drug in theU.S. but a quite effective antidepressant in use in other countries formany years. At a dose of 200 mg. Anafranil at bedtime, she got a veryminimal lifting of depression but was able to sleep. Months later, shepresented, having discontinued the Anafranil some time before but thennoted a return of increased depression and insomnia.

Restarting the Anafranil improved her sleep but little else. Trexan wasadded at a dose of 50 mg. daily in the morning and from three to fiveweeks after beginning this regimen, she noted a dramatic lifting of thedepression.

After a period on full doses of Anafranil, Anafranil was slowlywithdrawn stopping at 50 mg. of the antidepressant at night. She had amoderate reduction in mood but insisted that she still had an impressiveresult compared to post-treatment.

The Trexan was given at night instead of in the morning and sheexperienced an immediate return of depression and of special note, areturn of what she described as obsessive thoughts and behaviors.Reinstatement of the Trexan in the morning resulted in immediate returnof the ameliorative effect on depression and the cessation of obsessivethinking.

The patient was returned to treatment with 150-200 mg. Anafranil atnight and 50 mg. Trexan in the morning with good results.

EXAMPLE 2

An obese woman in her thirties who had been hospitalized for recurrentmajor depressive symptoms requested treatment. She also had vegetativesigns and was frequently suicidal. She was treated with large doses ofamitriptyline (Elavil), fluoxetine hydrochloride (Prozac) and eventuallysertraline hydrochloride (Zoloft) with marginal effects. She then took alethal overdose of amitriptyline which she surprisingly survived. Duringher last hospital stay, a stimulant, Ritalin, was added in doses up to160 mg. daily because of her lifelong distractibility and schooldifficulties consistent with Attention Deficit Disorder. She feltmarkedly better on Ritalin plus Zoloft 150 mg. in the morning but stillcomplained of craving for sweets, a frequent side effect ofantidepressant therapy which in her case resulted in 100 lb., plus,weight gain. She was also taking substantial doses of alprazalom(Xanax). The combination allowed her to be out of a hospital andreasonably non-suicidal.

She was started on Trexan, 25 mg., in the morning without making anyother changes. Very rapidly she lost her craving for sweets and a weightloss effort which was stalled took off. She lost thirty pounds in threeweeks. After three weeks of Trexan augmentation she started to feel"Happy" and without prompting she discontinued all use of Xanax. Thedosage of Ritalin was then reduced. While on combination therapy ofZoloft, Ritalin and Trexan, the patient has had no suicide ideation andcontinues to report being happy.

The loss of a carbohydrate craving is also of note as this is one of themost prominent causes of non-compliance in depressed patients. She wasmaintained with Zoloft, Ritalin, and Trexan 50 mg. dosing in themorning.

EXAMPLE 3

An obese man with a history of chronic recurrent depressive episodesespecially characterized by explosive rage and a pervasive irritabilityrequested treatment. He had racing thoughts and frequent swings inenergy. In addition, he was subject to distractibility going backthrough early childhood. His diagnosis was Bipolar Mood Disorder, type2. He responded to Amitriptyline 200 mg. at bedtime augmented by LithiumCarbonate up to 900 mg. daily. He was pleased with his result notingdiminishing anger, better self control and was willing to live with thecraving for sweets which treatment brought out despite gaining about 80lbs. Then, 25-50 mg. of Trexan was added to his medicines taken in themorning and again after three to four weeks he noted a dramaticallybetter mood.

He reported, "This is strange. All my life I've been suspicious and havelooked at things expecting the worst. I have always been negative. NowI'm looking at things positively and it feels weird." He commented thathe no longer craved sweets and reported losing about 10 lbs. a week. Hesaid that his mood swings were gone and his anger was completely gone.This result was dramatically different than what was evident before theTrexan was added. He was then fired in a corporate downsizing andreported that he did not understand why he was just calmly going aboutthe transition rather than falling apart.

EXAMPLE 4

A recovering alcoholic about age sixty with a major depression requestednew treatment. He commented that he had not been happy for at leasttwenty five years. He was started on Zoloft, 50 mg. in the morning and10, 50 mg. Trexan tablets with the instruction to take 25 mg. eachmorning until he ran out. He had been taking lorazepam (Ativan) a 5 mg.four times a day for some time and was anxious that it be continued.After three weeks, he reported that the "Zoloft" was working and electedto stop taking the Trexan since he "couldn't feel it do anything". Hesaid he was feeling happy for the first time and that on his own he hadstopped taking the Ativan except occasionally at night. One month later,he was not feeling quite as well and had resumed the full dose ofAtivan.

He was instructed that he may have responded better to the Zoloftearlier because of the concurrent use of Trexan and he consented torestart it. One month later he reported his depression was gone, and hadagain, without prompting, discontinued the use of Ativan.

EXAMPLE 5

A chronically depressed, agoraphobic woman requested treatment forrelief from severe suicidal depressive episodes. Due to her prominentphobic symptoms, she was started on imipramine 150-300 mg. at bedtimewith equivocal results. A shift to Anafranil at similar doses resultedin a significantly better lifting of her mood but she was still quiteimpaired and subject to mood swings. One weekend she called andrequested hospitalization due to very urgent wishes to kill herself. Shehappened to mention that Darvon would usually stop the urge to killherself and rather than put her in hospital, she was given Darvontemporarily.

She was then started on Trexan 25 mg. in the morning with imipramine andthree weeks later she felt "cured". Because of her concern aboutexpense, she stopped the Trexan without telling her physician andpresented again a few weeks later in a markedly depressed state despitecontinuing the imipramine. She was instructed to restart the Trexan andafter several weeks she had an enormously improved mood and a markedreduction in her agoraphobic symptoms. In this lady, concurrentantidepressant with naltrexone was necessary to prevent likelihood oflosing the patient to suicide or a return of severe depression.

EXAMPLE 6

A fifty-some year old man with recurrent episodes of depression andexplosive rage was being treated with imipramine for some three monthsprior to being admitted to the hospital. He was already tying the ropearound his neck when the police grabbed him. Three weeks after addingTrexan at 25 mg. in the morning to imipramine 175 mg. at bedtime, hebegan to describe a lifting of his depression and irritability andbecame quite social and lively.

EXAMPLE 7

A woman in her mid-thirties who had a leaking aneurysm requiringdestructive brain surgery and relearning to speak, was treated. She hada lifelong history of depression and had been deeply depressed whenseen. Treatment with 175 mg. of nortriptyline (Pamelor) for many monthshad resulted in equivocal improvement. After four weeks of Trexan 25 mg.in the morning with Pamelor, she began a marked and sustained remissionof depression described by the patient as the best ever.

EXAMPLE 8

An operating room nurse with a bipolar depression which resistedtricyclics, a-typical antidepressants, and lithium, alone, requestedtreatment. She was taking 600 mg. of Tegretal at bedtime when started onTrexan and was only taking the Tegretal to sleep. She had noantidepressant effect. She was then started on 50 mg. of Trexan withTegretal and she slept for three days. She was instructed to dissolvethe Trexan in water and take gradually increasing doses beginning withless than 2 mg. per day. She was able to increase to 25 mg. daily andafter several months became almost hypomanic, requiring periodicdiscontinuation of the Trexan to avoid becoming giddy on the job. Shereported that it was the first medicine combination she had taken thatimproved her mood reliably.

Tegretal is a tricyclic but an anticonvulsant/antimanic rather thanantidepressant.

EXAMPLE 9

It is expected that the patient of Example 8, above, would improve evenfurther if her treatment with Tegretal plus Trexan (25 mg.) wassupplemented or replaced with treatment administering lithium plus 25mg. Trexan. This latter combination would solve her problems dosingherself with Tegretal and Trexan intermittently correct her excessgiddiness or mania, while preventing depressive episodes.

What is claimed is:
 1. A method of treating depression associated withalcoholism, comprising administering to a patient a pharmacologicallyeffective dose of an opioid antagonist having a pentacyclic nucleusstructurally analogous to naltrexone, naloxone, and nalmefene, and aphatmacologically effective dose of an antidepressant compound selectedfrom the group consisting of a serotonin reuptake inhibitor, a tricyclicantidepressant, an atypical antidepressant, and lithiun, theirpharmacologically effective salts and esters, or combinations thereof.2. The method of claim 1, wherein said opioid antagonist is selectedfrom the group consisting of naltrexone hydrochloride, nalmefene, andthe salt and esters of nalmefene.
 3. The method of claim 1, wherein thepharmacologically effective dose of said opioid antagonist is a molarequivalent weight to 25 mg. of naltrexone hydrochloride.
 4. The methodof claim 1, wherein the pharmacologically effective dose of said opioidantagonist is a molar equivalent weight to 10 mg. of naltrexonehydrochloride.
 5. The method of claim 1 wherein said opioid antagonistand said antidepressant compound are administered using apharmaceutically acceptable carrier.
 6. The method of claim 1, whereinsaid antidepressant compound is selected from the group consisting ofbupropion, sertraline, fluoxetine, paroxetine, trazodone, and theirpharmacologically salts and ester, and combinations thereof.
 7. Themethod of claim 1, wherein said depressed patient is concomitantly beingtreated for a disorder selected from the group consisting of anxiety,mania, and convulsive disorder, wherein said anxiety disorder is beingtreated with a benzodiazepine compound, said mania is being treated withlithium and said convulsive disorder is being treated with ananticonvulsive active compound.